Mutations in the ncurofibromatosis type 1 gene (NF1) lead to a common genetic disorder that is identified by benign tumors of the peripheral nerves, hyperpigmentation, white matter lesions in the brain, learning disabilities, and many other manifestations (D. Viskochil et al., Annu. Rev. Neurosci. 16:183 (1993); F. McCormick, Curr. Opinion Genet. Dev. 5:51-55 (1995); K. North et al., Neurology 44:878 (1994)). The NF1 protein, which contains a fragment similar to the GTPase activating protein for Ras (Ras-GAP), stimulates the intrinsic activity of Ras-GTPase and therefore inhibits biological activation of Ras (G. F. Xu, et al., Cell 62:599 (1990); Cell 63:835 (1990); A. M. Buchberg etal., Nature 347.291 (1990); R. Ballester etal., Cell 63.851 (1990); G. A. Martin et al., Cell 63:843 (1990)).
The gene responsible for human neurofibromatosis type 1 (NF1) encodes a large protein that contains a central domain related to RasGAPs (S. M. Huson, et al., Brain 111:1355-1381 (1988); F. McCormick, Curr. Opin. Gen. Dev. 5:51-55 (1995); A. Bernards, Biochem. Biophys. Acta 1242:43-60 (1995)). Loss of NF1 expression correlates with increased Ras activity in several mammalian tumor cell types (T. N. Basu, et al., Nature 356:713-715 (1992); J. E. DeClue, et al., Cell 69:265-273 (1992); H. A. Kim et al., Oncogene 11:325-35 (1995); G. Bollag, et al., Nat. Genet. 12:144-8 (1996); D. A. Largaespada et al., Nat. Genet. 12:137-143 (1996)). However, the precise signaling pathways regulated by the NF1 protein remain poorly understood. Identification of such pathways would help to define molecular mechanisms underlying the extremely diverse symptoms observed in NF1 patients, which in addition to frequent benign and infrequent malignant tumors also include short stature and learning disabilities (S. M. Huson et al., Brain 111:1355-1381 (1988); F. McCormick, Curr. Opin. Gen. Dev. 5:51-55 (1995); A. Bernards, Biochim. Biophys. Acta 1242:43-60 (1995)).